Amino acid amidines and process of preparing same



Pat ented Aug- 19,

AMINO ACID AMIDINES AND PROCESS OF PREPARING SAME Karl Miescher and Willi Klarer, Biehen, and Ernst Urech, Basel, Switzerland. assignors. by

in Pharmacen mesne assignments, to Cl tical Products, Incorporated, Summit, N. 1., a corporationot New Jersey No Drawing. Application April 29, 1939, Serial No. 270,933. 'In Switzerland May '11, 1938 Claims. (o1. zeo-so'a) This invention relates to the manufacture of new amldines by causing a reactive ester of an oxyalkyl amidine to react with a primary or secondary amine.

The compounds thus obtained may be supposed to comprise the structure wherein A is an aminoalkyl radical containing a substituent at the nitrogen atom. The new amidines may be of open chain or cyclic form. .In the latter case the two amidine nitrogen atoms are united together by an allgvlene chaimfor in-.- stance as in the imidazoline or the tetrahydropyrimidine ring.

Among the reactive esters of oxyalkylamidines used as parent materials in the-invention there may be especially mentioned those derived from strong inorganic and organic acids, for instance hydrohalic acids or alkyl-sulionic acids or arylsulfonic acids. These amidines may be obtained by the reaction of an amine with the corresponding carboxylic acid derivative, for instance the imidoethers.

Any substituted primary or secondary amine is suitable for the reaction, forinstance, saturated and unsaturated alkylamine, alkylene diamines, alkanolamines, aralkylamines, aromatic or heteroc'yclic amines, for instance anilines, naphthylamines, amino-pyridines, aminoquinolines, aminobenzthiazoles or the like. There may also be used amines in which the nitrogen is; cyclicbound, as for instance in piperidine.

The invention affords a simple manner oi producing amino-acid amidines. The compounds produced are useful in therapeutics.

Cross reference is made to companion application Ser. No. 270,932, filed on even date herewith, which relates to the manufacture of new cyclic amidines by causing an amino acid having an aromatic or heterocyclic radical as a substituent at the nitrogen atom or a derivative thereoi to react with an aliphatic diamine.

The following examples illustrate the presen invention, the parts being by weight:

Example "1 CHr-CH:

CHr-C CHz-CH: NH,Hci

GER-CH1 CHPCL N Example 2 10.2 parts of Z-chlOromethylimidazoline (made from chloracetimido ether hydrochloride and ethylenediamine), 11.2 parts of n-dibutylamine and 25 parts of absolute alcohol are heated together to boiling for. a short time. After dis tilling the alcohol, the residuals dissolved in a little water and by adding alkali the 2-(ndibutylaminomethyl)-imidazo1ine thus produced separates in the tom of an oil. It may be disn i tilled at 123l25 C. in a vacuum of 0.6 mm. of Example 5 mercury 15.4 parts of fl-chloromethylimidazoline hydro- HN CH chloride and 28.6 parts of a-naphthylamine are 1- finely pulverized and well mixed together and the 1 m mixtureis heated for 1 hour at 70-75 C. The mass is then worked up as described in Example 3, whereby there is obtained the 2-(1-naphthylaoi-cne-o .noi+o,mon+ivm minomethyl) -i midazoline hydrochloride in the H I N form of transparent brownish crystals which melt e at 218-222? 0. /N--O H: v C4Ho N C H 9 l I c1-oH,-o .HCH- NH:

NE- E: cine NEPCH,

(34H, NCH: 1

/N*CH;C J .1501 NHCHr-C .HCl In like manner 2-laurylaminomethyl-imidazo- H line may be made.

f Example 3 Emmfl 6 parts of z'chlommethylmidazonne hydm' 9 parts of 2-chlorometliylimidazoline and 13 chloride and '28 parts of aniline are heated toparts fl d1ethy1 p phenylethylamme are I gether for 2 hours at 1004050 After coohng gether heated with 20 parts of alcohol for 1 hour the mixture is ground with ether whereby the at C and the alcohol is then removed in dlhydmchhride of'2'(pheny1ammmethy1)'imi' a vacuum. The residue is dissolved in water,

dazoline separates in the form of crystals. ThlS potassium carbonate is added to the solution dihydrochloride is soluble in water to an acid 50- which is then extracted by means of ether. The I i gg gd fig i ggggg igg -g i igiasfgggg x ethereal solution is separated. dried and evaptil the reaction is neutral, evaporating the neugiggl i zfi f gig fi i g zggg tral solution and recrystallizing the residue from 1 d 1th th y 1 1 t d a n h d alcohol there is obtained Z-(phenyiaminow 1d 3 w a 9 25 3 imethyl) -imidazoline hydrochloride which melts c nt e Y I p-phenylethylaminomethyl)-1midazoline hydroat 180-182 C.

v a chloride is obtained in the form of an oil which soon solidifies. It may be recrystallized from a ClCHz-C .HCH-CqH NH mixture of chloroform and ethyl acetate and tli'fi melts at 151-152" 0.

- N--oH,

GENE-Cliff! l o1'om-o .Hoi+c.H.o(o,Hor0mNm F H 11, Example 4 5 CuHr-C-(CaHOr-CHzNH-CH: 18.2 parts of Z-chloropropylimidazoline hydro- N--oH, chloride (made by the reaction of 'y-chlorobutyroimido-ether hydrochloride with ethylene dim amine; the imido-ether hydrochloride is obtained by the action of hydrogen chloride on a 50 The Same final p u ts are Obtained when mixture oil equivalent quantities of -chloroinstead of the hydrochloric acid esters the'hydrobutyronitrile and alcohol) and 28 parts of aniline bromic acid rs or the sulfonlc acid esters of are heated together for 2 hours at 105-110 C. the oxy lk mi in s are used.

The mass is then ground with ether, the portion In an analogous manner the following 0 insoluble in ether is dissolved in water and the P u s are made:

aqueous solution is mixed with alkali. This pre- Phenylammoacetammmemy cipitates the z-(phenylaminopro vdrochloride M. P. 135-137" 0. which melts at 63 C. and forms a hydrochloride Ph n l i a t i idin f melting at 1637164 C. no amidine-hydrochloride M. P. 148-150 C.

v N'HHCI HaN-OH: Phenylaminoacet p-phenyl .CPCHFCHHCHEC 1e illliglamidine hydrochlo- M P 145-146 C Jim-CH Z-methoxy-phenylaminoacetv 65 amidine-hydrochloride M. P. 19219-i C. ClCHzC-H:CH:C .Ho1+o,mon+mh 4-methoxy-pheny minoacetamidine-hydrochloride M. P. 199-200 C. r v. with decomposi- /N--GH: tion ol-onr-onr-om-o .Hoi+o.mNH, Z-g'fighOmpIhenIyiamiIno- V e azo ey- H drochloride M. P. 198-200 0.

B-methoxy-quinolyl-B-aminoo .1101 C'HNH OHr-CHPCHP acet-p-phenylethylamidine- '75 hydrochloride M. P, 146-147? c,

2-(G-methoxyquinolyM-amlnomethyD-imidazoline-hydrochloride......... ......a M. P. 193-195 C.

2-(B-methoxy-quinolyl-B-aminopropyil-imidazoline hydrochloride M. P. 230-232 C.

with decomposition What we claim is:

1. A process for the manufacture of amino aci a-midines, which comprises reacting a reactive ester of an oxyalkylimidazoline obtained by reacting the latter with a member of the group consisting of strong'organic and inorganic acidic substances, with an amine.

2. A process for the manufacture of amino acid amidines, which comprises reacting a reactive ester of an oxyalkylimidazoline obtained by reacting the latter with a member of the group consisting of strong organic andinorganic acidic substances, with an aromatic amine.

3. A process for the manufacture of amino acid amidines, which comprises reacting a reactive ester oi an oxyalkylimidazollne obtained by reacting the latter with a member of the group consisting of strong organic and inorganic acidic substances, with a heterocyclic amine.

l. A process for the manufacture oi amino acid smidines, which comprises reacting a reactive ester of an oxyalkylimidazoline obtained by reacting the latter with a member 0! the group consisting of strong organic and inorganic acidic KARL mESCI-IER.

WILLI KLARER. ERNST URECH. 

